Morphine as an opioid alkaloid in a poppy has been known from long since to have an effective analgesic effect and has been utilized with an aim of mitigating a keen pain typified in the terminal stage of cancer. However, since morphine has side-effects such as addiction, dependence, depression of respiration and constipation, it has drawbacks that its use is rather restricted and the way of use is difficult. In view of the above, it has been strongly demanded for the development of an analgesic having an analgesic effect equal or superior to morphine and showing no addiction such as morphine.
On the other hand, enkephalin which is an endogenic morphine-like substance (endogenic opioid) was found by J. Hughes et. al, in 1975 and it has been expected as a substance capable of substituting for morphine. However, it has been found that enkephalin and derivatives thereof involve drawbacks in that
(1) they are peptides and, accordingly, decomposed rapidly by enzymes in a living body, PA1 (2) they are poor in the BBB permeability and have to be administrated directly into a brain, and PA1 (3) they show similar side-effects to those of morphine such as addiction or dependence although they are endogenic substance.
For overcoming the foregoing drawbacks of the enkephalins, various studies have been made also at present but most of them have been directed to the enhancement of analgesic activity and moderation of the side-effects of the enkephalins in the vitro test or intraventricular administration test, as well as development for derivatives having high resistivity to decomposition by in vivo enzymes. In view of the foregoing situations, the present inventors have tried an improvement for the BBB permeability, which has not yet been studied by so much. Further, it has been expected that if the BBB permeability of the enkephalins can be improved, the BBB permeability of other substances with poor BBB permeability can also be increased to extend the application region.